Insights into the Regulation of Neurogenesis Termination and the Secretomes of Oligodendrocytes

Neurogenesis is a key process of neurodevelopment that requires intricate temporal regulation. While the regulation from embryonic to adult neurogenesis has been more actively characterized, the molecular mechanisms regulating the postnatal termination of neurogenesis and the disappearance of embryonic radial glia, the neural stem cells (NSCs) responsible for neurogenesis, are still largely unknown. In the first chapter, we investigated the role of transcription factor PR domain-containing 16 (Prdm16) using genetic mouse models and single-cell RNA sequencing. This work provides evidence on how conditional deletion of Prdm16 expression from NSCs extends the time span in which cortical neurogenesis occurs and alters the cellular composition of the ventricular sub-ventricular zone. Mechanistically, we determined that Prdm16 induces a postnatal reduction in Vascular Cell Adhesion Molecule 1 (Vcam1). We also showed that the extended presence of radial glia and neurogenesis phenotype was rescued in Prdm16-Vcam1 double conditional knockout mice. These findings demonstrate that inhibition of Vcam1 by Prdm16 promotes the postnatal termination of neurogenesis and the disappearance of embryonic radial glia. Similarly, the function of oligodendrocyte progenitor cells (OPCs) beyond their well-characterized contribution to myelination remains to be well characterized. OPCs and oligodendrocytes are a significant cell population in the brain, comprising around 22-28% of the total cells. OPCs remain present throughout life suggesting potential additional functions beyond their canonical role in generating oligodendrocytes. In the second chapter, I investigated the secreted proteome of OPCs and oligodendrocytes to elucidate additional functions these cells may have in homeostatic and inflammatory conditions. Using an in vitro model of purified rat OPCs and oligodendrocytes, I found that both OPCs and oligodendrocytes secrete various extracellular matrix proteins under physiological conditions suggesting they may play a larger role in extracellular matrix production and remodeling than previously described. Similarly, following cytokine treatment, I found both OPCs and oligodendrocytes secretion of immunoregulators such as C2 and B2M providing evidence that these cells have an active role in the inflammatory response possibly through cross-talk with other glial and immune cells via signaling molecules like C2 and B2M. These findings shed light on OPCs and oligodendrocytes having a more active role in regulating their environment via the proteins they secrete, highlighting their multifaceted function beyond their established myelin-forming roles. Together these findings contribute novel insights into molecular regulators of neurogenesis termination and the functions of OPCs and oligodendrocytes. The novel finding of Prdm16 has a repressor of Vcam1 expression in radial glia fills a critical gap in our understanding of neural stem biology and offers valuable knowledge for future regenerative medicine efforts aimed at treating central nervous system disorders. Likewise, the unbiased secretome of OPCS and oligodendrocytes highlights several avenues for further investigation into these cells as modulators of the ECM and the inflammatory response